Development of hemodiafiltration therapy--a historical perspective.

Hemodiafiltration (HDF) was created in the late 1970s to combine the best of hemodialysis (HD) and hemofiltration, i.e. superior removal of both small and large solutes. Thus, optimal conditions for both diffusion and convection are required. The need for large volumes of sterile fluid has shaped the evolution of HDF, and regulatory issues around systems for on-line fluid preparation have delayed the clinical development of the therapy. Not until such systems became generally available in the mid-1990 s was it possible to increase the efficiency of HDF therapy to match and exceed the upgrade that had taken place for HD. Results from recent studies indicate that the potential for improving the outcome of dialysis lies in increasing the convective clearance of HDF above that of high-flux HD.

The economic issue of on-line hemodiafiltration within the Japanese medical reimbursement system.

One major issue of Japan's health care system is that the Ministry of Health, Labor and Welfare (MHLW) centrally decides on the prices of medical services. Because of this, even if a treatment is deemed superior by the actual medical service provider, it may not be economically feasible to carry out. On-line hemodiafiltration has been reported to be an effective and favorable treatment modality, but the number of treated patients has declined since its approval in 2010 due to its low reimbursement price determined by MHLW. In this way, the problem with the Japanese medical reimbursement system is that MHLW's policy measures can thus affect the details of actual medical practices.

Polysulfone: the development of a membrane for convective therapies.

The polysulfone membrane was developed as a membrane for convective dialysis therapies at the beginning of the 1980s. The target was to produce a higher-permeable membrane on the basis of synthetic polymers, such as polysulfone. The development of a membrane with high permeability went hand in hand with a technology development that finally presented as an essential precondition for the success of the polysulfone membrane. This article describes the development phase of the polysulfone membrane using to-date unpublished extracts of the project report of the polysulfone membrane and commenting these from today's perspective.

Historical milestones of a long pathway.

Hemodiafiltration (HDF), developed from the combination of hemodialysis and hemofiltration, is considered to be the most effective current procedure to remove uremic toxins from the blood of kidney patients. Historically, the clinical use of HDF was for many years limited due to the cost burden related to the large amount of sterile volume replacement fluid needed. The solution offered was on-line preparation of replacement fluid from standard dialysate by means of membrane filtration. Industry opened to this concept quite early and worked on various technical solutions between the early 1980s and the late 1990s before real state-of-the-art systems became commercially available on a broad basis. This article reviews in particular the activities of initially Fresenius and later Fresenius Medical Care in this field and identifies major concepts and prototypes up to today's commercially available high-end product--the 5008 therapy system--where on-line HDF finally became integrated as a standard component.

The machine and the therapy concept.

Maintenance haemodialysis became established in mainstream clinical practice in the 1960s. For pragmatic reasons, diffusive dialysis was the technique which underpinned its success. Over the next 15 years it was shown that short- and medium-term survival depended only on a critical level of urea clearance being achieved. Uncomplicated technology with negligible capacity for middle molecule removal could deliver this and the case for developing more sophisticated machines able to broaden the spectrum of solute removal was unconvincing. Dialysis-related amyloidosis which was recognised in the mid-1980s as a devastating complication in long survivors disturbed this complacency. The journey to develop machines which could deliver broad-spectrum solute removal while exposing patients only to ultrapure fluids and biocompatible materials is described elsewhere in this text. The Lister Renal Unit was established in 1988. A fruitful collaboration between the multidisciplinary clinical team and engineering colleagues in the R&D Department of Fresenius contributed to a steady and in-depth understanding of the effect of superimposing convection on diffusive dialysis. From the outset only high-flux dialysis using ultrapure fluids was employed. Haemodiafiltration (HDF) was introduced in 1993. This paper summarises our observations regarding the relative contributions of natural renal function and convective blood purification to long-term outcomes. We have recently reported a 19-year experience which has allowed us to more clearly define the rationale for HDF in modern clinical practice. HDF is an engineering triumph which is likely to universally supersede diffusive dialysis. The challenge for clinicians moving forward is to learn in which treatment schedules this technology can best be deployed to improve the health prospects of patients with kidney failure.

The early years of on-line HDF: how did it all start? How did we get here?

In the mid-1980s, limits and side effects of contemporary hemodialysis were basically due to short treatment time, use of low-flux membranes and employment of acetate-buffered dialysate. These were already associated with a relatively high morbidity and cardiovascular mortality as part of diaysis-related pathology. Based on these considerations, the concept of on-line hemodiafiltration (HDF) was proposed as an innovative solution. By combining diffusive and convective clearances, HDF offered the most efficient modality to clear small and middle-sized uremic toxins. Furthermore, by using ultrapure dialysis fluid and high-flux synthetic membranes, HDF also offered the most biocompatible dialysis system, thereby going a long way towards preventing inflammation. Through provision of virtually unlimited amounts of sterile dialysis fluid by cold sterilization of fresh dialysate, on-line HDF offered an economical and viable method of conducting high-efficiency HDF (high volume exchange) therapy. By keeping the hemodialysis machine with all built-in technical options (e.g. adjustable blood pump, fluid-balancing system, conductivity meter, flow and pressure monitoring, bicarbonate-buffered dialysate), HDF benefited from being associated with the use of dialysis machines with excellent technology as well as highest safety standards. Use of ultrapure water made it then possible to produce dialysis fluid of intravenous grade quality with these machines. The first on-line HDF clinical trial was performed with a modified A2008C dialysis machine in 1984-85. This confirmed the feasibility and potential of the on-line HDF method. Some 25 years later, on-line HDF has proven to be safe, efficacious and with clinical benefits that justify it becoming a new standard for high-quality care of chronic kidney patients.

Fifteen years of experience with on-line hemodiafiltration.

Hemodiafiltration (HDF) with elevated substitution fluid offers an optimal way of removing uremic substances. The beginnings of HDF and on-line HDF, learning curve, differences in the removal of uremic toxins, difficulties in the development, automated manual Q(i) as a practical way of prescribing, distinct experiences with on-line HDF and prospective, randomized ongoing on-line HDF studies are detailed as a personal vision for 15 years' handling with on-line HDF.

Dawn of hemodiafiltration.

A brief history of hemodialysis, hemofiltration and hemodiafiltration (HDF) is reviewed with special interest on the development of HDF, including development of dialysis/ultrafiltration membranes, ultrafiltration rate controllers, dialysis fluid delivery systems, and guidelines for water quality required for online HDF treatment.

Review Article: is it time to embrace haemodiafiltration for centre-based haemodialysis?

Improvements in survival in dialysis patients over the past few decades have been disappointing. Recent prospective trials such the haemodialysis study have not shown conclusive improvements. Two recent observational studies have found a striking survival advantage for haemodiafiltration (HDF). This review covers the differences between HDF and conventional haemodialysis (HD) and the history of the technological advances in the HDF technique. In addition, it explores the putative benefits of HDF over HD. While the observational studies provide a basis for optimism that HDF will provide benefit to dialysis patients, definitive conclusions cannot be drawn until the results of randomized controlled trials are available. While the evidence in favour of HDF at this stage is observational only, there are no studies suggesting that the treatment is detrimental. The use of HDF should probably be increased, particularly in centres where an increase in the frequency and duration of dialysis cannot be readily achieved.